The overall goals of this proposal are, (1) to investigate the effects of in utero opiate dependence and withdrawal in the fetus, and (2) to establish an animal model in which to investigate placental drug transfer and pharmacokinetics. In studying the pharmacologic and physiologic effects of opiate dependence and withdrawal, the primary drug effects of opiate withdrawal in the fetus will be separated from the secondary effects of maternal opiate withdrawal on the fetus. The animal model will be the chronically catheterized pregnant ewe because of the relative ease of catheterizing the fetus and the growing body of information about the physiology of the fetal lamb. Opiate dependence will be produced by a continuous intravenous infusion of morphine sulfate to the mother. Comparisons will be made between the maternal and fetal responses to the injection of naloxone (a specific opiate antagonist) and abrupt (natural) opiate withdrawal. I have studied the independent fetal response to an intravenous injection of naloxone into the fetus 24 to 96 hours after initiating an infusion of morphine to its mother. This response includes elevations in fetal systolic and diastolic arterial blood pressures, and decreases in fetal heart rate, arterial blood PO2 and pH. The mother had no response to the injection of naloxone into the fetus. Intravenous injection of naloxone into the mother resulted in elevations in maternal systolic and diastolic arterial blood pressures and no changes in heart rate or arterial blood gasses and pH. The fetal response to injecting the mother with naloxone was comparable to that observed when it received naloxone directly. Experiments are outlined to produce maternal opiate dependence without fetal dependence by the simultaneous infusion of morphine to the mother and naloxone to the fetus. The specific effects of maternal withdrawal on the fetus can be observed. Studies designed to compare fetal to neonatal opiate withdrawal in the lamb are also proposed. In addition, a model of maternal-placental-fetal drug transfer will be tested. These experiments will determine the rates of transfer of morphine from the mother to the fetus and from the fetus to the mother. The rate of placental elimination of morphine as the drug passes in both directions will be determined. Future studies of drug transfer will compare drugs with varying physico-chemical properties.